Chronic myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell malignancies characterized by excessive production of blood cells. Polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (MF) are the three most common BCR/ABL1-negative MPNs and are associated with thrombosis and hemorrhage, splenomegaly, and the risk of transformation to acute myeloid leukemia.
The classification of myeloproliferative neoplasms (MPN) has focused on specific disease-defining, mutually exclusive translocations and mutations in key growth regulatory genes. Some of these genetic alterations are tightly associated with prior clinically-defined entities, such as BCR-ABL1 rearrangement in chronic myeloid leukemia (CIVIL) and JAK2 exon 12 mutations in polycythemia vera (PV). Other mutations, such as JAK2 V617F, myeloproliferative leukemia gene (MPL) mutations and colony-stimulating factor 3 receptor (CSF3R) mutations, have also been found to be associated with MPN (Cazzola et al. Blood 2014 Jun. 12; 123(24):3714-9).
Somatic mutations in the chaperone gene calreticulin (CALR) have been identified in essential thrombocythemia (ET) and primary myelofibrosis (PMF), and are essentially mutually exclusive with JAK2 and MPL mutations (Klampfl et al. N. Eng J Med 2013 Dec. 19; 369(25):2379-90; Lundberg et al. Blood 2014 Apr. 3; 123(14):2220-8; Nangalia et al. N Engl J Med 2013 Dec. 19; 369(25):2391-405; Tefferi et al. Leukemia 2014 July; 28(7):1568-70; Vannucchi et al. Leukemia 2014 September; 28(9):1811-8). These CALR mutations are localized to exon 9 of the CALR gene and are largely specific for ET and PMF, being found only rarely in cases of myelodysplasia. Normal and mutant CALR proteins can differentially affect the subcellular trafficking of JAK-STAT signaling components (Rampal et al. Blood 2014 May 29; 123(22):e123-e133). The two most common disease-associated CALR mutations in ET and PMF are a 52-base pair (bp) deletion at codon 367 (type 1) and a 5-bp TTGTC insertion at codon 385 (type 2). Both produce a +1 bp frameshift that generates novel C-terminal protein sequences with a shift from acidic to basic amino acid residues, which is believed to affect chaperone activity (Rizvi et al. Mol Cell 2004 Sep. 24; 15(6):913-23). Other +1 bp frameshift mutations (types 3-30) and 3 in-frame exon 9 deletions (Ensembl TMP_ESP_19_13054649 E393_E395del3, and TMP_ESP_19_13054685 and COSM3355757 (p.E405_408) have also been described (Klampfl et al. N Engl J Med 2013 Dec. 19; 369(25):2379-90).